Variations of neuronal nitric oxide synthase in systemic sclerosis skin

Abstract

Objective. In systemic sclerosis (SSc), derangement of the peripheral nervous system is linked to vascular tone dysfunction. Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS, NOS-I) might play a dynamic role in the control of vascular tone. This study was performed to verify, by immunohistochemical and biochemical analyses, the presence and expression of nNOS and protein gene product 9.5 (PGP 9.5) in SSc skin, in different subsets and various phases of the disease.Methods. Biopsy samples of clinically involved skin from 32 SSc patients (12 with limited cutaneous SSc [lcSSc] and 20 with the diffuse form [dcSSc]) and skin samples from 6 healthy controls were either immunostained with anti-PGP 9.5 and anti-nNOS antibodies or analyzed by semiquantitative reverse transcriptionpolymerase chain reaction and Western blotting.Results. Immunohistochemical and biochemical data showed a decrease in PGP 9.5 and nNOS innervation and in their messenger RNA (mRNA) levels in lcSSc and dcSSc skin. In the edematous phase of SSc, a light alteration in cutaneous innervation was initiated and slowly progressed into the sclerotic phase, becoming most evident in the atrophic phase. Levels of nNOS mRNA were significantly lower between the edematous phase and the sclerotic phase in both dcSSc and lcSSc skin, which was attributable to the earlier occurrence of more severe pathologic alterations.Conclusion. Total cutaneous innervation and nNOS innervation slowly disappear in the skin of SSc patients. Expression of nNOS depends on the severity of tissue damage in SSc, and increased synthesis of NO also contributes to this process. It remains to be determined whether the changes in cutaneous innervation are due to the disease itself or whether these changes contribute to the pathogenesis and evolution of SSc.

Lymphatic and blood vessels in scleroderma skin, a morphometric analysis

“…The glands and the other skin appendages have been shown to be preserved, although reduced in number, even in the advanced skin pattern of the disease [29]. VEGF-C is expressed in the immature cells of sebaceous glands in an animal model of cutaneous wound healing [19].…”

Recent Advances on Pathogenesis and Therapies in Systemic Sclerosis

“…Total cutaneous innervation and nNOS innervation slowly disappear in the skin of SSc patients [36]. Expression of nNOS depends on the severity of tissue damage in SSc, and increased synthesis of NO also contributes to this process [36]. Although previous studies have reported that circulating concentrations of most angiogenic factors were significantly higher in patients with SSc, there are no clear explanation for these elevation.…”

“…NO produced by neuronal nitric oxide synthase (nNOS, NOS-I) might play a dynamic role in the control of vascular tone. Total cutaneous innervation and nNOS innervation slowly disappear in the skin of SSc patients [36]. Expression of nNOS depends on the severity of tissue damage in SSc, and increased synthesis of NO also contributes to this process [36].…”

Sparing effect of hemiplegia on skin fibrosis and microvascular involvement: Reports of two cases of systemic sclerosis and review of the literature

“…A large body of evidence has demonstrated that NO plays a key role in SSc physiologic and pathologic events, yet still controversial: either positive or negative effects at the microvascular level have been found in SSc skin [66]. Interestingly, besides the impairment of endothelial and inducible NO synthase activity in SSc [67,68], skin neuronal NO synthase was found to be down-regulated [69], and sympathetic skin impairment might have a role. In a recent study on a mouse model for hemiplegia-induced protection from RA, an impact on microvasculature was hypothesized [70].…”